Research: The encapsulated bacteria, H. influenzae type b (Hib), pneumococci, and meningococci are important bacterial pathogens in certain high risk groups including malignancy, particularly splenectomy for staging of Hodgkin's disease, and acute leukemia, as well as children with asplenia, immunodeficiency, or belonging to certain ethnic groups. A critical determinant of susceptibility is the ability of the host to make antibody to the capsular polysaccharides of these pathogens. We have previously shown that immunoglobulin (Ig) allotypes, antigenic variants of Ig heavy and light chains, are correlated with anti-polysaccharide antibody responses and risk of H. influenzae type b infections in healthy Caucasians. The proposed studies will extend these observations to high risk groups including Hodgkin's disease, acute leukemia, and to the Native Americans, a population known to have a 10 to 100 fold increased risk of invasive Hib and pneumococcal infections. The Ig allotypes of these groups will be correlated to antibody response to polysaccharides and for the Native Americans correlated with disease susceptibility as well as the anti-capsular antibody response to colonization, immunization and natural infection. To further examine Ig allotype associated regulation of the anti-polysaccharide antibody response in normal adults, Ig allotypes will be correlated with the Ig G subclass distribution, the light chain distribution, and affinity of antibody to polysaccharides. Using isoelectric focusing and fine specificity criteria we will examine the heterogeneity of the human anti-polysaccharide response and the relationship to allotypes. Finally, in a family study of Ig G-2 deficient children, we will correlate response to polysaccharide immunization with HLA type, complotypes, and allotypes. The aim will be to characterize any abnormalities in the antibody response, the pattern of heritability of these abnormalities and to examine for an association with the genetic markers. These findings will be important for the evaluation of the immunogenicity and efficacy of new bacterial vaccines since genetically indentifiable groups may contribute disproportionately to disease incidence. Elucidation of regulatory mechanisms may provide clues to new approaches for the development of more immunogenic vaccines for these high risk groups.